US4384140A - 2-Chloroethyl urea derivatives - Google Patents

2-Chloroethyl urea derivatives Download PDF

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Publication number
US4384140A
US4384140A US06/348,724 US34872482A US4384140A US 4384140 A US4384140 A US 4384140A US 34872482 A US34872482 A US 34872482A US 4384140 A US4384140 A US 4384140A
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United States
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group
chloroethyl
carbon atoms
atoms inclusive
dimethylamino
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Expired - Fee Related
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US06/348,724
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English (en)
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Peter Bregnedal
Jorn L. M. Buus
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Kefalas AS
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Kefalas AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
    • C07C275/68—N-nitroso ureas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the preferred compounds of this invention are those of Formula I, in which X and Y are unsubstituted phenyl groups or phenyl groups having fluorine atoms at the para-position, "Alkylene” is a trimethylene group, optionally substituted with a methyl group in the 2-position, and R 1 and R 2 are methyl groups.
  • the present invention also includes pharmaceutically acceptable acid addition salts of the compounds of Formula I. Such salts are easily prepared by methods known to the art.
  • the base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or methanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or methylene chloride, with the desired salt separating directly.
  • an aqueous miscible solvent such as acetone or methanol
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic (pamoic), succinic, oxalic, bis-methylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, flutamic, benzene sulfonic and theophylline acetic acids as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • inorganic salts of the compounds of Formula I are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • these salts may also be prepared by the classical method of double decomposition of appropriate salts which is wellknown to the art.
  • the compounds of Formula I and the non-toxic acid addition salts thereof may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
  • the present invention moreover comprises a method for the preparation of the novel nitrosourea derivatives of Formula I whereby a compound of the following formula: ##STR2## wherein X, Y, R 1 , R 2 and "Alkylene" are as defined above, is nitrosated in acid medium to yield the compound of Formula I which is isolated either as the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • the nitrosation may according to the invention preferably be carried out in well-known manner by using sodiumnitrite in acid medium, such as formic acid solution, hydrochloric acid solution, glacial acetic solution, or the like.
  • acid medium such as formic acid solution, hydrochloric acid solution, glacial acetic solution, or the like.
  • NO 2 - -anion formed by reduction of the NO 3 - -anion in situ by means of copper in for example glacial acetic acid solution.
  • the starting materials of Formula II are also novel compounds and form part of this invention. They may according to the invention conveniently be prepared according to the following scheme: ##STR3## In all these reactions are X, Y, R 1 , R 2 and "Alkylene" as defined above.
  • the starting material N-(2-Chloroethyl)-N'-(2,2-bis(4-fluorophenyl)-5-(dimethylamino)pentyl)urea, was prepared in the following way:
  • the combined etherphases were extracted twice with 250 milliliters of 2 N hydrochloric acid and the combined aqueous phases made alkaline to pH 10 with sodium hydroxide solution (28%).
  • the base which separated out was extracted with 1000 milliliters of diethyl ether, the ether solution dried over anhydrous magnesium sulfate and evaporated on a heating bath at 50 degrees centigrade.
  • the residue was dissolved in 500 ml acetone/ethanol, 99% (1:1), and oxalic acid was added until pH 3.
  • M.P. 85-87 degrees centigrade.
  • the precipitate which crystallized out consisted of 22 grams of N-(2-chloroethyl)-N'-(2,2-bis(4-fluorophenyl)-5-(dimethylamino)pentyl)urea melting at 205-210 degrees centigrade after washing with diethyl ether.
  • N-(2-chloroethyl)-N'-(2,2-diphenyl-5-(dimethylamino)pentyl)urea was prepared in the following way:
  • N-(2-chloroethyl)-N'-((2,2-diphenyl)-4-methyl-5-(dimethylamino)-pentyl)urea was prepared in the following way:
  • Example 1 When Example 1 was carried out using 3-chloro-N,N,2-trimethylpropylamine instead of 3-chloro-N,N-dimethylpropylamine there were obtained as intermediates:
  • N-(2-chloroethyl)-N'-(2,2-bis(4-fluorophenyl)-4-methyl-5-(dimethylamino)pentyl)urea M.P.: 132-134 degrees centigrade.
  • Lu 16-035 and Lu 16-022 were tested against the following tumors:
  • Lu-16-035 and Lu-16-022 have shown a significant to good effect.
  • BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea
  • the drugs are administered intraperitonally (i.p.) in a single dose on day one after the implantation of the tumor in the mice.
  • the drugs are administered i.p. on day 1.5 and 9 after the tumor implantation in the mice.
  • the drugs are administered in one daily dose from day 1 to 9 after implantation of the tumor.
  • Lu 16-035 and Lu 16-022 have better effects than BCNU on some tumors, and that they show a more favorable therapeutic index.
  • the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof may be administered to animals such as dogs, cats, horses, sheep or the like, including human beings, both orally and parenterally, and may be used for example in the form of tablets, capsules, powders, syrups or in the form of the usual sterile solutions for injection.
  • each dosage unit containing a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of from about 1 to about 100 mg, most preferably, however, from about 10 to 50 calculated as the free amine.
  • the compounds of Formula I are usually administered in intervals of from four to ten weeks.
  • the exact individual dosages in a particular case will, of course, be determined according to established medical principles under the direction of a physician.
  • the dosage range for such cytostatic drugs is usually given as weight per squaremeter of body area and normally falls within from about 10 to about 200 milligrams per squaremeter of body area.
  • the active ingredient is for the most part mixed with ordinary tablet adjuvants such as corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, or the like.
  • the acid when isolating the compounds of Formula I in the form of an acid addition salt the acid is preferably selected so as to contain an anion which is non-toxic and pharmacologically acceptable, at least in usual therapeutic doses.
  • Representative salts which are included in this preferred group are the hydrochlorides, hydrobromides, sulphates, acetates, phosphates, nitrates, methanesulphonates, ethane-sulphonates, lactates, citrates, tartrates or bi-tartrates, embonates and maleates of the amines of Formula I.
  • Other acids are likewise suitable and may be employed if desired.
  • Fumaric, benzoic, ascorbic, succinic, salicylic, bismethylenesalicylic, propionic, gluconic, malic, malonic, mandelic, cinnamic, citraconic, stearic, palmitic, itaconic, glycolic, benzenesulphonic, and sulphamic acids may also be employed as acid addition saltforming acids.
  • the invention also comprises a method for the alleviation, palliation, mitigation or inhibition of the manifestations of certain physiological-psychological abnormalies of animals by administering to a living animal body, including human beings, an adequate quantity of a compound of Formula I or a non-toxic acid addition salt thereof.
  • An adequate quantity would be from about 5 mg to about 100 mg per squaremeter of body area in each unit dosage, and from about 15 milligrams to about 300 milligrams/squaremeter of body area every fourth to sixth week.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/348,724 1979-10-03 1982-02-16 2-Chloroethyl urea derivatives Expired - Fee Related US4384140A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB7934306 1979-10-03
GB7934306 1979-10-03

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US06/191,910 Division US4367239A (en) 1980-09-29 1980-09-29 Nitrosourea derivatives, pharmaceutical compositions thereof and method of preparation

Publications (1)

Publication Number Publication Date
US4384140A true US4384140A (en) 1983-05-17

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US06/348,724 Expired - Fee Related US4384140A (en) 1979-10-03 1982-02-16 2-Chloroethyl urea derivatives

Country Status (12)

Country Link
US (1) US4384140A (no)
EP (1) EP0026989B1 (no)
JP (1) JPS5657762A (no)
AT (1) ATE7137T1 (no)
AU (1) AU539986B2 (no)
DE (1) DE3067553D1 (no)
DK (1) DK417380A (no)
FI (1) FI802903A (no)
IE (1) IE50228B1 (no)
NO (1) NO150316C (no)
NZ (1) NZ194777A (no)
ZA (1) ZA805421B (no)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962524A (en) * 1997-12-24 1999-10-05 Caster Depigmenting composition
US9102599B2 (en) 2006-12-01 2015-08-11 Bristol-Myers Squibb Company N-((3-benzyl)-2,2-(bis-phenyl)-propan-1-amine derivatives as CETP inhibitors for the treatment of atherosclerosis and cardiovascular diseases

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8205324L (sv) * 1982-09-17 1984-03-18 Leo Ab Nya n-nitrosoforeningar, kompositioner innehallande sadana foreningar, framstellningsforfaranden och behandlingsmetoder
GB8500615D0 (en) * 1985-01-10 1985-02-13 Lundbeck & Co As H Organic compounds
CA2163325A1 (en) * 1994-11-21 1996-05-22 Kaneyoshi Kato Amine compounds, their production and use
WO1998043628A1 (fr) * 1997-04-02 1998-10-08 Viktor Veniaminovich Tets Remede antitumoral (chlonidane)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Hori et al., CA 91:211367s, (1980). *
Nakas et al., CA 79:53186c, (1973). *
Saikawa et al., CA 90:54978b, (1979). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962524A (en) * 1997-12-24 1999-10-05 Caster Depigmenting composition
US9102599B2 (en) 2006-12-01 2015-08-11 Bristol-Myers Squibb Company N-((3-benzyl)-2,2-(bis-phenyl)-propan-1-amine derivatives as CETP inhibitors for the treatment of atherosclerosis and cardiovascular diseases

Also Published As

Publication number Publication date
IE50228B1 (en) 1986-03-05
NZ194777A (en) 1983-06-14
EP0026989A2 (en) 1981-04-15
NO150316C (no) 1984-10-03
DE3067553D1 (en) 1984-05-24
AU539986B2 (en) 1984-10-25
DK417380A (da) 1981-04-04
EP0026989B1 (en) 1984-04-18
FI802903A (fi) 1981-04-04
AU6291180A (en) 1981-04-09
NO802925L (no) 1981-04-06
IE801789L (en) 1981-04-03
JPS5657762A (en) 1981-05-20
EP0026989A3 (en) 1981-06-24
NO150316B (no) 1984-06-18
ZA805421B (en) 1981-09-30
ATE7137T1 (de) 1984-05-15

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